Visual function depends on the intimate structural, functional and metabolic interactions between the retinal pigment epithelium (RPE) and the neural retina. Photoreceptor (PR) cells have a high rate of metabolism that is supported through a continuous supply of glucose and oxygen from the choroidal vasculature. The RPE forms the outer blood retinal barrier and transports glucose to the outer retina via GLUT1 transporters in both the apical and basolateral membranes. The RPE spares glucose for the outer retina by oxidizing lactate generated through aerobic glycolysis in the outer retina and fatty acids derived from ingested photoreceptor outer segments (OS). Thus, we hypothesize that the RPE serves as the gatekeeper of retinal metabolic stability through bioenergetics specializations that enhance retinal fuel availability and support photoreceptor function. In this role, it is critical that RPE function be maintained over a lifetime, especially given that these cells are post-mitotic. RPE oxidation of fatty acids and lactate maintains its differentiation and PR function as changes in oxidative metabolism lead to RPE dedifferentiation. We hypothesize that the beneficial effects of fatty acid oxidation (FAO) working in synergy with ketogenesis will (1) provide energy for the RPE and prevent steatosis (2) reoxidize mitochondrial NADH to facilitate lactate utilization, (3) decrease RPE reliance on glucose thereby sparing it for the neural retina and (4) provide fuel for PR through ketolysis of ?HB. Furthermore, we hypothesize that lactate is not only a fuel for energy production in RPE, but by-products of lactate oxidation regulate lysosomal pH and gene transcription. Our long-term goal is to identify the pathways that control metabolic symbiosis in the outer retina to sustain normal vision over a lifetime. The hypotheses will be tested in the following specific aims. Specific aim 1: To determine whether oxidation of long chain fatty acids is necessary to maintain metabolic homeostasis and differentiation of the RPE. Specific Aim 2: To determine how the coordinated activities of RPE ketogenesis and PR ketolysis support visual function. Specific Aim 3: To determine whether lactate produced through aerobic glycolysis in PR and M?ller glia in the outer retina supports RPE metabolism and differentiation as well as maintenance of lysosomal pH. Collectively these studies demonstrate the symbiotic relationship among the metabolically specialized cells in the outer retina. Damage to the RPE, PR or M?ller cells can cause non-autonomous changes that negatively affect the entire system and lead to vision loss.